Bladder cancer is the fourth most common cancer in the United States. In 2007, about 67,160 new cases of bladder cancer will be diagnosed and 13,750 patients will die of these diseases. Transitional cell carcinoma accounts for more than 90% of bladder cancers. Approximately 70-80% of bladder cancer patients present with superficial tumors. Superficial bladder cancer is managed usually by transurethral resection of the tumor with or without fulguration, and adjuvant intravesical chemotherapy. Between 40 to 80% of patients treated by transurethral resection develop recurrent tumors, and between 10 to 20% of recurrent disease present with grade and/or stage progression. Intravesical immunotherapy and chemotherapy reduces the disease recurrence rate. Through a series of preclinical and clinical studies, an important lesson learned is that the efficacy of intravesical mitomycin (MMC) or doxorubicin therapy is limited by two factors, i.e., inadequate drug delivery to tumor cells and low chemosensitivity of the more rapidly proliferating tumors. We subsequently identified an optimized method to enhance the delivery of MMC to superficial bladder tumors, and tested this method in a randomized, two-arm NCI-supported international phase III trial in 14 academic centers. The results confirm our hypothesis that maximizing the MMC delivery significantly improves the recurrence-free rate, from 23% in the standard arm to 43% in the optimized arm. This substantial improvement highlights the importance of adequate drug delivery in this treatment modality. The remaining challenge is to develop an effective treatment for the remaining patients (~60%) who cannot be managed by intravesical MMC. During the Phase I SBIR grant, we evaluated several drug carriers and identified paclitaxel-loaded gelatin nanoparticles (PNP) as the candidate. The completed in vitro and in vivo studies showed favorable drug release and bladder tissue penetration properties, and significant antitumor activity. The goal of the previous Phase I SBIR grant was to develop a formulation of paclitaxel suitable for intravesical treatment. An added advantage of selecting paclitaxel is due to (a) it has activity against bladder cancer, (b) it is lipophilic and therefore can readily partition across the urothelium, (c) it binds to tissues and therefore is retained beyond the 2-hr duration of the intravesical therapy, and (d) it can induce apoptosis through p53-dependent and -independent pathways and is therefore active in tumors with wild type p53 or mutated p53 activity against p53. The activity in p53-mutated tumors is desirable as 60% of bladder tumors has mutated p53 and because MMC induces apoptosis through p53-dependent pathways and is therefore not active against tumors with mutated p53. Studies conducted during the phase I R43 grant support the use of intravesical PNP for the treatment of superficial bladder cancer. The present phase II SBIR application is directed at advancing the development of PNP toward clinical evaluation. We proposed to conduct cGMP manufacturing, analysis and testing to meet FDA requirement, GLP preclinical toxicology, pre-IND meeting with FDA, final IND filing, and design of clinical development strategy. PUBLIC HEALTH RELEVANCE:The current proposal is to develop a novel therapeutic approach to treat cancer, with a focus on bladder cancers in particular.